93: Sex Dependent Contribution of CGRP? to Pain and Disease Processes in Mice with Knee Arthritis

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic primary musculoskeletal pain, , , , , , Transgenic models, Behavioral studies, , ,

Background and Aims: Osteoarthritis is the most common cause of chronic pain and disability in the U.S impacting nearly 20% of the U.S. population over 45 years of age (1, 2). Knee OA is a progressive disorder characterized by persistent synovial inflammation, fibrosis, cartilage degeneration and bone structural changes leading to severe pain and disability. While OA affects both men and women, women make up approximately 60% of OA cases and have worse clinical outcomes compared to men (3). Despite this knowledge, very few preclinical studies have examined potential sexual dimorphism present in pain or cellular processes associated with the development of knee arthritis (4).

Methods: We crossed TRPV1-Cre mice with Calca fl/fl mice to achieve selective knockdown of CGRPα in sensory neurons. The effects of CGRPα depletion on pain related behavioral outcomes including primary (knee) hyperalgesia and secondary (hindpaw) allodynia were assessed in male and female mice following knee joint inflammation (intra-articular CFA) and following joint injury (partial medial meniscectomy, PMX) The effect of CGRPα knockdown on immune cell activation, fibrosis and angiogenesis in the knee joint were assessed using multi-plex immunohistochemistry and histology. Bone structural changes within the femoral and tibial subchondral bone of the knee joint were assessed longitudinally using radiography.

Results: We observed a significant reduction of primary hyperalgesia and secondary allodynia in sensory neuron selective CGRPα deficient female, but not male mice with knee inflammation. In female mice with knee CFA, CGRPα deficiency reduced macrophage infiltration and markers of fibrosis but did not alter the density of blood vessels in joint synovium/fat pad compared to wild type female mice. Radiographically, no obvious differences were observed in the subchondral bone between genotypes in female mice with knee inflammation. CGRPα deficient female mice also displayed reduced hyperalgesia following PMX surgery compared to wild type female mice.

Conclusions: Our data provide evidence that CGRPα deficiency results in significant pain-relieving effects in female mice with knee inflammation and following joint injury. Pain relieving effects of CGRPα deficiency in female mice are likely due to effects on disease related processes including modulation of immune cell and fibroblast activation within the knee joint. Future studies will determine the contribution of sensory neuron immune and fibroblast crosstalk to pain and disease processes in knee OA utilizing genetically modified mice that allow for cell type selective blockade of CGRPα signaling in combination with scRNAseq of knee joint tissue.

References: 1. Wallace IJ, Worthington S, Felson DT, Jurmain RD, Wren KT, Maijanen H, Woods RJ and Lieberman DE. Knee osteoarthritis has doubled in prevalence since the mid-20th century. Proc Natl Acad Sci U S A 2017; 114: 9332-9336. 2017/08/16. DOI: 10.1073/pnas.1703856114.

2. Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, Gabriel S, Hirsch R, Hochberg MC, Hunder GG, Jordan JM, Katz JN, Kremers HM, Wolfe F and National Arthritis Data W. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008; 58: 26-35. 2008/01/01. DOI: 10.1002/art.23176.

3. Segal NA, Nilges JM and Oo WM. Sex differences in osteoarthritis prevalence, pain perception, physical function and therapeutics. Osteoarthritis Cartilage 2024; 32: 1045-1053. 2024/04/09. DOI: 10.1016/j.joca.2024.04.002.

4. Dvir-Ginzberg M, Maatuf YH and Mobasheri A. Do we understand sex-related differences governing dimorphic disease mechanisms in preclinical animal models of osteoarthritis? Osteoarthritis Cartilage 2024; 32: 1054-1057. 2024/03/27. DOI: 10.1016/j.joca.2024.03.113.

Presenting Author: Christopher M.Peters
Submitting Author: Christopher Peters

Senior Author: Christopher M. Peters

IASP 2026 Global Year theme of Neuropathic Pain: No

• Renee Parker: MPH - Wake Forest University Medical School
• Edgar Alfonso Romero-Sandoval: MD, PhD - Wake Forest University Medical School
• Yusuke Shiozawa: MD, PhD - Wake Forest University Medical School
• Juan Miguel Jimenez-Andrade: PhD - Autonomous University of Tamaulipas Reynosa
• Thomas Jeffrey Martin: PhD - Wake Forest University Medical School
• Alejandro Pluma-Pluma: PhD - Wake Forest Un-versity Medical School
• Mariana Galvanaguilar: B.S. - Wake Forest University Medical School
• Sun Hee Park: PhD - Wake Forest University Medical School
• Daniela Fernandez: B.S. - Wake Forest University Medical School
• Christopher M. Peters: PhD - Wake Forest University Medical Center